Ponatinib promotes a G1 cell-cycle arrest of merlin/NF2-deficient human schwann cells

Neurofibromatosis type 2 (NF2) is a genetic syndrome that predisposes individuals to multiple benign tumors of the central and peripheral nervous systems, including vestibular schwannomas. Currently, there are no FDA approved drug therapies for NF2. Loss of function of merlin encoded by the NF2 tumor suppressor gene leads to activation of multiple mitogenic signaling cascades, including platelet-derived growth factor receptor (PDGFR) and SRC in Schwann cells. The goal of this study was to determine whether ponatinib, an FDA-approved ABL/SRC inhibitor, reduced proliferation and/or survival of merlin-deficient human Schwann cells (HSC). Merlin-deficient HSC had higher levels of phosphorylated PDGFRα/β, and SRC than merlin-expressing HSC. A similar phosphorylation pattern was observed in phospho-protein arrays of human vestibular schwannoma samples compared to normal HSC. Ponatinib reduced merlin-deficient HSC viability in a dose-dependent manner by decreasing phosphorylation of PDGFRα/β, AKT, p70S6K, MEK1/2, ERK1/2 and STAT3. These changes were associated with decreased cyclin D1 and increased p27Kip1levels, leading to a G1 cell-cycle arrest as assessed by Western blotting and flow cytometry. Ponatinib did not modulate ABL, SRC, focal adhesion kinase (FAK), or paxillin phosphorylation levels. These results suggest that ponatinib is a potential therapeutic agent for NF2-associated schwannomas and warrants further in vivo investigation

Traumatic facial nerve injuries: review of diagnosis and treatment

Both blunt and penetrating craniofacial trauma may lead to severe facial nerve injury and sequelae of facial paralysis. Initial evaluation involves quantitation of motor deficits using a clinical grading system, such as the House-Brackmann scale. High resolution computed tomography is used for localization of nerve injury in suspected cases of temporal bone trauma. In the absence of gross radiographic abnormalities, electrophysiologic testing helps predict the likelihood of spontaneous recovery. In patients with deteriorating facial nerve injuries by electroneuronography, surgical exploration is the preferred management. Primary end-to-end neurorrhaphy is the preferred management for transection injuries, while facial nerve decompression may benefit other forms of high-grade nerve trauma. Secondary facial reanimation procedures, such as cranial nerve crossovers, dynamic muscle slings or various static procedures, are useful adjuncts when initial facial nerve repair is unsuccessful or impossible. A review of facial nerve trauma management and case illustrations are presented

Tympanic membrane breakdown after intratympanic injection of steroids in irradiated ears

To describe a rare complication of intratympanic injection of steroids in susceptible ears. We present two patients with a history of irradiation involving the injected ear. Therapeutic. Tympanic membrane condition after intratympanic injection of steroids. Total or near-total breakdown of the irradiated tympanic membrane. Tympanic membranes with an impaired wound-healing ability, together with exposure to intratympanic steroids, may be at risk for total or near-total breakdown

Blast Injuries to the Facial Nerve

The recommended treatment of penetrating traumatic facial nerve injuries associated with Immediate, total paralysis of the ipsilateral facial muscles generally includes facial nerve exploration and repair. We reviewed our experience with bullet injuries to the extratemporal facial nerve to determine the efficacy of this approach. Five patients with immediate, total facial nerve paralysis caused by bullet wounds near the extratemporal facial nerve were seen between July 1990 and December 1992. Of four patients who underwent surgical exploration, only one demonstrated complete transection of the facial nerve. Two of these four were followed up with serial electroneuronography, which demonstrated complete degeneration within the first week after injury. The fifth patient was followed up with serial electroneuronography without complete degeneration, and partial recovery was observed. We conclude that penetrating bullet injuries with immediate, total facial paralysis may not necessarily be associated with transection of the facial nerve. We propose a method of treating patients with these Injuries using electroneuronography

Long-Term Efficacy of Endolymphatic Sac Surgery for Vertigo in Meniere's Disease

The long-term efficacy of endolymphatic sac procedures for control of vertigo in Melnere's disease has been controversial. We evaluated results of sac shunt surgery for 234 patients having at least 10 years followup (mean, 13.5 years). All patients had persistent vestibular symptoms despite medical therapy. All underwent endolymphatic subarachnoid shunt as their original operation. Data were collected by chart review and questionnaire regarding: (1) the number of additional surgical procedures to control vertigo, (2) remaining dizziness, and (3) level of disability. One hundred forty-seven of the patients (63%) did not undergo any further surgery to control vertigo, and an additional 17% had only revisions of the endolymphatic sac shunt. Thus, 80% never required a destructive procedure. Long-term effectiveness of surgery in regard to dizziness and disability was determined from the questionnaire. Of the 147 patients with only the original sac shunt surgery, 93% reported no dizziness or mild to no disability. Of the group who underwent only revisions of the original shunt, 96% stated they had no more dizziness or mild to no disability. We conclude that endolymphatic sac shunt operations are effective as Initial surgical procedures for long-term control of disabling vertigo of Meniere's disease